Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis

James Yarmolinsky, Emmanouil Bouras, Caroline J Bull, Emma E Vincent, Richard M Martin, Olympia Dimopoulou, Sarah J Lewis, Marc J Gunter, Kostas Tsilidis

Research output: Contribution to journalArticle (Academic Journal)peer-review

6 Citations (Scopus)

Abstract

Aims/hypothesis
Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk.

Methods
We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10−8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as ‘strong’ and ‘weak’ evidence.

Results
In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10−3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints.
Original languageEnglish
Pages (from-to)1481-1500
Number of pages20
JournalDiabetologia
Volume66
Issue number8
DOIs
Publication statusAccepted/In press - 13 Mar 2023

Bibliographical note

Funding Information:
The work of Epidemiological investigations of the chances of preventing, recognizing early and optimally treating chronic diseases in an elderly population (ESTHER)/VERDI was supported by grants from the Baden-Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. In the Harvard cohorts, Health Professionals Follow-Up Study (HPFS) is supported by the NIH (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, and R35 CA197735), Nurses’ Health Study (NHS) by the NIH (P01 CA087969, UM1 CA186107, R01 CA137178, R01 CA151993, and R35 CA197735), and Physicians’ Health Study (PHS) by the NIH (R01 CA042182). The Hawaii Adenoma Study is supported by NCI grant R01 CA72520. The Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC) is supported by grants from Chonnam National University Hwasun Hospital, HCRI15011-1. In Kentucky, work was supported by a Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8) and grant NCI R01CA136726. The Leeds Colorectal Cancer Study (LCCS) was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. Multiethnic Cohort (MEC) was supported by NIH grants (R37 CA54281, P01 CA033619 and R01 CA063464). The work of Molecular Epidemiology of Colorectal Cancer (MECC) was supported by the NIH, US Department of Health and Human Services (R01 CA081488, R01 CA197350, U19 CA148107, R01 CA242218) and a generous gift from Daniel and Maryann Fong. The work of Memorial Sloan Kettering Cancer Center (MSKCC) at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt was supported by funding from the NIH (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). We acknowledge funding support for NCCCS I & II from the NIH, R01 CA66635 and P30 DK034987. This work of Newfoundland Colorectal Cancer Registry (NFCCR) was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821), the NIH, US Department of Health and Human Services (U01 CA74783), and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of A. Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to M. O. Woods by the Canadian Cancer Society Research Institute. The Northern Swedish Health and Disease Study (NSHDS) research was supported by Biobank Sweden through funding from the Swedish Research Council (VR 2017-00650, VR 2017-01737), the Swedish Cancer Society (CAN 2017/581), Region Västerbotten (VLL-841671, VLL-833291), Knut and Alice Wallenberg Foundation (VLL-765961), and the Lion’s Cancer Research Foundation (several grants) and Insamlingsstiftelsen, both at Umeå University. Ohio State University Medical Center (OSUMC) Ohio Colorectal Cancer Prevention Initiative (OCCPI) funding was provided by Pelotonia and HNPCC funding was provided by the NCI (CA16058 and CA67941). The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics were supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For SEARCH, the University of Cambridge has received salary support in respect of PDDP from the NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge also provided support. SELECT research reported in this publication was supported in part by the National Cancer Institute of the NIH under Award Numbers U10 CA37429 (C. D. Blanke) and UM1 CA182883 (C. M. Tangen/I. M. Thompson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The work of Screening Markers For Colorectal Disease Study and Colonoscopy and Health Study (SMS-REACH) was supported by the National Cancer Institute (grant P01 CA074184 [to J. D. Potter and P. A. Newcomb], grants R01 CA097325, R03 CA153323 and K05 CA152715 [to PAN]) and the National Center for Advancing Translational Sciences at the NIH (grant KL2 TR000421 [to ANB-H]). The Swedish Low-risk Colorectal Cancer Study was supported by grants from the Swedish Research Council (K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2) and the Stockholm County Council (ALF project). The Swedish Mammography Cohort and Cohort of Swedish Menwas supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute´s Distinguished Professor Award to A. Wolk. UK Biobank research has been conducted using the UK Biobank Resource under Application Number 8614. VITamin D and OmegA-3 TriaL (VITAL) was supported by NIH (K05 CA154337). The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung and Blood Institute, NIH, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C.

Funding Information:
The authors would like to thank the participants of the individual studies contributing to the BCAC and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for their participation in these studies, along with the principal investigators of these consortia for generating the data used for this analysis and for making these data available in the public domain. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)-specific acknowledgements include French Association STudy Evaluating RISK for Sporadic Colorectal Cancer (ASTERISK); we are very grateful to B. Buecher without whom this project would not have existed. We also thank all participants in this study, as well as all the physicians, technicians and students. The CCFR graciously thanks the generous contributions of their study participants and acknowledge the dedication of study staff and the financial support from the US National Cancer Institute, without which this important registry would not exist. The authors would like to thank the study participants and staff of the Seattle CCFR and the Hormones and Colon Cancer study (CORE Studies). We thank the participants of Clue II and appreciate the continued efforts of the staff at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the Clue II Cohort Study. The authors would like to thank the COLON and NQplus investigators at Wageningen University & Research and the involved clinicians in the participating hospitals. We kindly thank all individuals who agreed to participate in the Colorectal Cancer Study of Austria (CORSA) study. Furthermore, we thank all cooperating physicians and students and the Biobank Graz of the Medical University of Graz. The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results programme. For the Czech Republic Colorectal Cancer Study (CCS), we are thankful to all clinicians in major hospitals in the Czech Republic, without whom the study would not have been practicable. We are also sincerely grateful to all participants in this study. We thank all participants and cooperating clinicians in Darmkrebs: Chancen der Verhütung durch Screening (DACHS), and everyone who provided excellent technical assistance. We acknowledge all contributors to the development of the Early Detection Research Network (EDRN) resource at University of Pittsburgh School of Medicine, Department of Gastroenterology, Department of Pathology, Hepatology and Nutrition and Biomedical Informatics. For European Prospective Investigation into Cancer and Nutrition (EPIC), where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/WHO. We are sincerely grateful to all participants who were recruited as part of the EPICOLON project. We acknowledge the Spanish National DNA Bank, Biobank of Hospital Clínic–IDIBAPS and Biobanco Vasco for the availability of the samples. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona. For the Harvard cohorts (HPFS, NHS, PHS), the study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T. H. Chan School of Public Health, and those of participating registries as required. We acknowledge Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital as home of the NHS. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities and cancer centres. Participating central cancer registries include Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia and Wyoming. The authors assume full responsibility for analyses and interpretation of data from these registries. We would also like to acknowledge the staff at the Kentucky Cancer Registry. We acknowledge the contributions of Jennifer Barrett, Robin Waxman, Gillian Smith and Emma Northwood in conducting the Leeds Colorectal Cancer Study (LCCS) study. We would like to thank North Carolina Case-Control Study (NCCCS) I and NCCCS II study participants, and the NC Colorectal Cancer Study staff. Northern Swedish Health and Disease Study (NSHDS) investigators thank the Västerbotten Intervention Programme, the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, the Biobank Research Unit at Umeå University and Biobanken Norr at Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council. The authors thank the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial screening centre investigators and the staff from Information Management Services Inc and Westat Inc. Most importantly, we thank the study participants for their contributions that made this study possible. Cancer incidence data have been provided by the District of Columbia Cancer Registry, Georgia Cancer Registry, Hawaii Cancer Registry, Minnesota Cancer Surveillance System, Missouri Cancer Registry, Nevada Central Cancer Registry, Pennsylvania Cancer Registry, Texas Cancer Registry, Virginia Cancer Registry and Wisconsin Cancer Reporting System. All are supported in part by funds from the Center for Disease Control and Prevention, National Program for Central Registries, local states, or by the National Cancer Institute, Surveillance, Epidemiology and End Results programme. The results reported here and the conclusions derived are the sole responsibility of the authors. We thank the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) team. We thank the research and clinical staff at the sites that participated in the Selenium and Vitamin E Prevention Trial (SELECT) study, without whom the trial would not have been successful. We are also grateful to the 35,533 dedicated men who participated in SELECT. The authors thank the Women’s Health Initiative (WHI) investigators and staff for their dedication, and the study participants for making the programme possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf

Publisher Copyright:
© 2023, The Author(s).

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